The development of unconventional oil and gas resources is increasingly shifting toward heterogeneous reservoirs with complex permeability distributions, making the effective control of hydraulic frac Show more
The development of unconventional oil and gas resources is increasingly shifting toward heterogeneous reservoirs with complex permeability distributions, making the effective control of hydraulic fracture propagation patterns critical for optimizing production. To this end, this study establishes a 3D multilayered heterogeneous reservoir model using the finite element method to analyze fracture mechanisms. The impacts of permeability heterogeneous, injection rate, and fracturing fluid viscosity on fracture morphology are systematically investigated, and the elasticity coefficient method was used to evaluate the influence weights of each parameter.The main conclusions are as follows: (1) Permeability distribution is the core factor controlling the fracture propagation direction, with HPL dominating the extension path while MPL and LPL show limited efficiency. (2) An increase in the number of permeability layers inhibits the overall expansion of cracks, and the shape of the cracks gradually changes to rectangular. (3) Higher injection rates significantly expand fracture area, whereas fracturing fluid viscosity ≥50 mPa·s stabilizes fracture morphology. (4) The elastic coefficient method identifies injection rate, permeability heterogeneous, and fracturing fluid viscosity as the key control parameters in order. This work provides theoretical guidance for optimizing hydraulic fracturing parameters in complex geological settings. Show less
No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations. This cross-sectional study included Chinese patients ( Chinese HCM Show more
No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations. This cross-sectional study included Chinese patients ( Chinese HCM patients have a higher proportion of rare variants (52.8% vs 13.6%, Our findings suggested that patients of Chinese ancestry with HCM have a higher proportion of rare variants but are less likely to be classified as P/LP variants in HCM genes than those of European origin. The variants of c.3624del in Show less
The mediation effect of 24-hour physical activities on the association between type 2 diabetes and mortality is unclear. Additionally, Little evidence was found on the isotemporal substitution effect Show more
The mediation effect of 24-hour physical activities on the association between type 2 diabetes and mortality is unclear. Additionally, Little evidence was found on the isotemporal substitution effect of 24-hour physical activities components on changing Life expectancy among patients with type 2 diabetes diagnosed. To address the abovementioned research gap, the study has a two-fold aims: first, to examine the mediation effect of 24-hour physical activities in type 2 diabetes and mortality; and second, to address how reallocating time on different daily activities would affect life expectancy. Analysis was conducted on the accelerometer data of 103,359 participants in the UK Biobank, with a median age of 57 years (range 39 to 70). Compositional mediation cox model was conducted to analyze the mediating effects of 24-hour physical activities. Additionally, the cohort Life table method was utilized to estimate the changes of Life-years over the next 10 years resulting from the substitution effect of different physical activities. During a mean follow-up of 13.95 (range 2.95-16.28) years, 2,649 deaths were recorded. Diabetes was significantly associated with increased time spent engaging in sedentary behavior (SB), and reduced time spent on moderate-to-vigorous physical activity (MVPA) and light-intensive physical activity (LPA), thereby demonstrating an association with higher mortality risk. The indirect effect of physical activity (HR = 1.27, 95% CI 1.23-1.30) accounted for 41.9% of the total effect of diabetes on mortality. Furthermore, the Life expectancy gains with a maximum of 1.32 years over the next 10 years was found when reallocating SB time to MVPA. The results revealed that 24-hour physical activities might mediate the association between diabetes and mortality. Therefore, promoting participation in MVPA and reducing sedentary activities among diabetes patients was expected to have a positive effect on Life expectancy over the next 10 years. Show less
Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury and inflammation. It is reported that profibrogenic signals released from stressed/injur Show more
Sustained activation of hepatic stellate cells (HSCs) drives liver fibrosis in response to chronic liver injury and inflammation. It is reported that profibrogenic signals released from stressed/injured hepatocytes evoke fibrogenic responses in HSCs. However, intrahepatocyte players that modulate such cell-to-cell communications remain poorly defined. In this study, hepatic ChREBPα is found to be reduced in mouse models of chemical-induced liver fibrosis as well as in three groups of human patients with liver fibrosis. Chrebpα-LKO mice are highly sensitive to both chemical (CCL4 and TAA) and bile duct ligation (BDL)-induced liver injury and developed more advanced liver fibrosis without affecting liver lipid content. Hepatocyte ChREBPα overexpression suppressed the activation of HSCs in an in vitro medium transfer experiment in part via inhibiting the expression of profibrogenic factors THBS1 and CTGF. RNA-Seq analysis revealed that E2F1, a novel effector of TGFβ-mediated fibrogenic pathway, is highly induced in the liver of Chrebpα-LKO mice. Hepatic knockdown of E2F1 ameliorated the increased liver fibrosis in mice with hepatic Chrebpα deficiency while reducing the expression of hepatic THBS1 and CTGF. Show less
For small ruminants, meat quality-an economically significant characteristic-results from the combined effects of genetic, dietary, and physiological elements. However, the contribution of gastrointes Show more
For small ruminants, meat quality-an economically significant characteristic-results from the combined effects of genetic, dietary, and physiological elements. However, the contribution of gastrointestinal (GI) tract gene expression to meat quality remains unclear. Here, we performed bulk RNA-seq on 130 samples from Liangshan Black Sheep and Meigu Black Goats, including 10 GI tract segments and semitendinosus muscle, integrating these data with measurements of amino acid composition, fatty acid profiles, and volatile flavor compounds. We found distinct, segment-specific transcriptional programs across the GI tract, with major functional shifts at the rumen-reticulum, omasum-abomasum, and abomasum-duodenum transitions. In the ileum and jejunum, genes involved in lipid metabolism showed links to fatty acid profiles, whereas genes governing amino acid metabolism in the small intestine were connected to the amino acid composition of muscle. Cecum- and colon-enriched genes were linked to flavor precursor biosynthesis. Species-specific differences revealed that sheep muscle contained higher levels of key amino acids (Asp, Glu, Hyp, Cys, Tyr), whereas goats showed higher α-linolenic acid and other polyunsaturated fatty acids. This work establishes a gut-muscle transcriptomic axis in small ruminants, identifying candidate genes (e.g., Show less
Coelonin is a dihydrophenanthrene compound derived from the traditional Chinese medicine Bletilla striata (Thunb.) Reichb.f., which exhibits significant anti-inflammatory activity and effectively inhi Show more
Coelonin is a dihydrophenanthrene compound derived from the traditional Chinese medicine Bletilla striata (Thunb.) Reichb.f., which exhibits significant anti-inflammatory activity and effectively inhibits lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 cells. Although previous studies have demonstrated the protective effect of Bletilla striata against LPS-induced acute lung injury (ALI), the potential protective role and underlying molecular mechanisms of its major active component, Coelonin, in ALI remain unclear. In this study, an LPS-induced mouse ALI model was established to systematically evaluate the protective effects of Coelonin on ALI. Furthermore, transcriptomic analysis was utilized to investigate the anti-inflammatory mechanisms mediated by Coelonin through the regulation of non-coding RNA (ncRNA)-associated inflammatory pathways. The results indicated that Coelonin significantly ameliorated LPS-induced pathological damage in lung tissues and markedly reduced the levels of inflammatory markers in bronchoalveolar lavage fluid (BALF). In vitro experiments using the murine alveolar macrophages (MH-S) cell line further confirmed the anti-inflammatory activity of Coelonin. Transcriptome analysis revealed that Coelonin markedly upregulates the expression of the ncRNA Gm27505, which was previously found to be downregulated in a mouse model of Alzheimer's disease. To date, there have been no reports on the biological functions of Gm27505. Bioinformatics analysis and real-time quantitative fluorescence PCR (qPCR) confirmed that this ncRNA is primarily localized within the nucleus. Overexpression of Gm27505 in MH-S cells significantly downregulated the expression of inflammation-related genes such as Il6, Tnfα, Il27, and Ccl3 induced by LPS stimulation. Moreover, overexpression of Gm27505 promoted macrophage polarization toward the M2 phenotype while suppressing M1 polarization. These findings suggest that the ncRNA Gm27505 plays an important biological role and is critically involved in the regulation of inflammatory responses. Coelonin may alleviate LPS-induced ALI in mice by up-regulating Gm27505 expression and modulating macrophage polarization. Therefore, Gm27505 may represent a potential target for the prevention and treatment of ALI, providing new research directions for future therapeutic strategies against related diseases. Show less
Patients with cancer undergoing cisplatin chemotherapy frequently experience cardiotoxic side effects that significantly affect their prognosis and survival rates. Our study found that Panax ginseng r Show more
Patients with cancer undergoing cisplatin chemotherapy frequently experience cardiotoxic side effects that significantly affect their prognosis and survival rates. Our study found that Panax ginseng root extract exerted a significant protective effect against cisplatin-induced myocardial cell injury. The present study aims to elucidate the underlying mechanisms by which the bioactive components of Panax ginseng mitigate cisplatin-induced cardiotoxicity (CIC). In vitro, the candidate active components were screened by network pharmacological prediction and in neonatal rat ventricular myocytes (NRVMs), and their mechanisms of action were verified by transcriptome sequencing, western blotting, gene overexpression, immunoprecipitation, immunofluorescence, and cellular thermal shift assays. A C57BL/6 CIC mouse model was established to verify the protective effects of the candidate components and the in vivo mechanism of the candidate components. Through network pharmacology prediction and cellular activity screening of ginseng root compounds, ginsenoside Rh2(S) (Rh2) was identified as a significant active component. Transcriptomic, in vitro, and in vivo experiments demonstrated that Rh2 can activate the Pak1/Limk1/cofilin phosphorylation pathway, thereby inactivating the actin-severing protein cofilin and protecting cardiomyocytes from cisplatin-induced actin depolymerization. Additionally, Rh2 suppressed the ROS/caspase-3/GSDME pathway to inhibit cisplatin-induced pyroptosis. Furthermore, co-immunoprecipitation and overexpression experiments confirmed that Rh2 activated the FGFR1/HRAS axis, thereby simultaneously regulating the two aforementioned pathways to combat CIC. This study demonstrated for the first time that Rh2 is the main active component in Panax ginseng that maintains cytoskeletal homeostasis and inhibits pyroptosis by regulating the FGFR1/HRAS pathway to resist CIC. This study aimed to provide a theoretical basis for expanding the targets and pathways of CIC treatment, and for the development of related drugs. Show less
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offe Show more
Accelerated population aging and rising incidence of bone defects have intensified the need for advanced bone regeneration strategies. While tissue-engineered scaffolds fabricated via 3D printing offer promising alternatives to conventional grafts, most techniques fail to replicate the multi-scale fibrous architecture of native bone extracellular matrix, limiting their biofunctionality. To address this, we developed a hybrid manufacturing strategy integrating low-temperature thermally induced phase separation with extrusion-based 3D printing of polylactic acid (PLA) scaffolds. By optimizing solvent ratios (THF: DMF = 3:1) and freezing temperatures (-196 °C-4 °C), we produced scaffolds with tunable micro-nano fibrous surfaces and macroporous structures. Key findings revealed that scaffolds processed at -196 °C (PLA-196) exhibited the highest porosity (pore size: 6.01 ± 2.06 μm), superior hydrophilicity, and enhanced compressive modulus. These scaffolds significantly promoted BMSC adhesion, proliferation, and osteogenic differentiation via activation of Show less
Fibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergen Show more
Fibrotic remodeling of nucleus pulposus (NP) leads to structural and mechanical anomalies of intervertebral discs that prone to degeneration, leading to low back pain incidence and disability. Emergence of fibroblastic cells in disc degeneration has been reported, yet their nature and origin remain elusive. In this study, we performed an integrative analysis of multiple single-cell RNA sequencing datasets to interrogate the cellular heterogeneity and fibroblast-like entities in degenerative human NP specimens. We found that disc degeneration severity is associated with an enrichment of fibrocyte phenotype, characterized by CD45 and collagen I dual positivity, and expression of myofibroblast marker α-smooth muscle actin. Refined clustering and classification distinguished the fibrocyte-like populations as subtypes in the NP cells - and immunocytes-clusters, expressing disc degeneration markers HTRA1 and ANGPTL4 and genes related to response to TGF-β. In injury-induced mouse disc degeneration model, fibrocytes were found recruited into the NP undergoing fibrosis and adopted a myofibroblast phenotype. Depleting the fibrocytes in CD11b-DTR mice in which myeloid-derived lineages were ablated by diphtheria toxin could markedly attenuate fibrous modeling and myofibroblast formation in the NP of the degenerative discs, and prevent disc height loss and histomorphological abnormalities. Marker analysis supports that disc degeneration progression is dependent on a function of CD45 Show less
Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood. In this study, we used a mouse model of hemorrhagic s Show more
Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood. In this study, we used a mouse model of hemorrhagic stroke induced by autologous blood injection to investigate the effects of acupuncture on post-stroke recovery at the cellular and molecular levels, utilizing single-cell RNA sequencing. Our findings revealed that acupuncture modulates the gene expression of microglia, astrocytes, and oligodendrocytes, three major glial cell types, which may contribute to the improvement of stroke-induced phenotypes. Notably, we identified a potential role of the APOE-TREM2 signaling axis, with ligand-binding interactions enhancing microglia activation and promoting their neuroprotective functions. These findings also suggested that acupuncture may promote microglia-astrocyte interactions, leading to enhanced neuroinflammation resolution and tissue repair. Our study provided new insights into the cellular mechanisms underlying acupuncture's therapeutic effects in stroke recovery and highlighted the potential of targeting glial cell-mediated pathways, including APOE-TREM2, as a strategy for improving post-stroke rehabilitation. Show less
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for Show more
Biomarker profiling from biofluids such as blood are widely measured in clinical research, using for example Olink proteomics panels. One such research focus area is cardiovascular disease (CVD), for which chronic sleep restriction (SR) is a risk factor. However, it remains unclear whether blood levels of commonly measured CVD biomarkers are sensitive to acute dynamic factors such as SR, physical exercise (PEx), and time of day. In this crossover design, 16 normal-weight, healthy men underwent three highly standardized in-lab nights of SR (4.25 h/night) and normal sleep (NS, 8.5 h/night) in randomized order, with 88 CVD blood protein biomarkers quantified using the Olink technology (and selected validation using ELISA) in the morning, evening, and immediately before and repeatedly after 30 min of high-intensity exercise. We found significant time-of-day-dependent changes in several CVD biomarkers. Whereas several proteins were exercise-induced across sleep conditions (such as the canonical exerkines IL- 6 and BDNF), exercise-induced proteomic dynamics differed in response to recurrent SR, compared with following NS. Moreover, SR compared with NS resulted in a biomarker profile previously associated with increased prospective risk of several CVDs across large-scale cohorts (such as higher circulating levels of IL-27 and LGALS9). Our findings highlight how dynamic physiology can modulate CVD biomarker levels. These results also underscore the need to consider sleep duration as a key determinant of cardiovascular health-an emphasis reflected in recent American Heart Association guidelines. Further studies in women, older individuals, and patients with prior CVD, and across different chronotypes and dietary schedules are warranted. Show less
This study aimed to compare the diagnostic value of [ A prospective study was conducted between March 2023 and July 2023. Patients with high clinical suspicion of lung cancer were recruited. Each part Show more
This study aimed to compare the diagnostic value of [ A prospective study was conducted between March 2023 and July 2023. Patients with high clinical suspicion of lung cancer were recruited. Each participant underwent PET/CT scanning using [ A total of 101 participants were included (mean age 63.267 ± 9.344 [range 39-86 years]). In benign lung lesions, [ [ Show less
Sarcopenia is a common age-related skeletal muscle disorder that lacks diagnostic and therapeutic options. Emerging evidence suggests that cuproptosis, a copper-dependent form of regulated cell death, Show more
Sarcopenia is a common age-related skeletal muscle disorder that lacks diagnostic and therapeutic options. Emerging evidence suggests that cuproptosis, a copper-dependent form of regulated cell death, contributes to muscle atrophy, yet the underlying associations remain poorly understood. To address this gap, we integrated two GEO datasets (GSE1428 and GSE25941) for differential expression analysis and applied weighted gene co-expression network analysis (WGCNA) to identify disease-related modules. Cuproptosis-related genes (CRGs) from GeneCards database were intersected with DEGs and WGCNA gene modules to obtain sarcopenia-associated cuproptosis DEGs (SAR-CUP DEGs). Functional enrichment was performed using GO, KEGG, GSEA and GSVA. Hub genes were further identified through three machine learning algorithms (LASSO, RF, and SVM). Regulatory networks were constructed via NetworkAnalyst and GeneMANIA database. A diagnostic model was also developed and later validated in an independent dataset (GSE136344). Experimental validation was performed in a D-galactose-induced sarcopenia cell model. We identified 367 DEGs and 7 co-expression modules, among which 14 SAR-CUP DEGs were mainly enriched in mitochondrial energy metabolism pathways. Machine learning methods highlighted Show less
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immun Show more
Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immunotherapy remains unexplored. We integrated bulk and single-cell RNA sequencing data from TCGA, GEO, and scRNA-seq datasets to analyze IL27RA expression, prognosis, immune infiltration, and treatment response. TIDE and immune checkpoint-treated clinical cohorts were used to assess immunotherapy responsiveness. Chemotherapy sensitivity was predicted using GDSC data, and IL27RA protein expression was validated by Western blot. IL27RA was downregulated in breast cancer but high expression correlated with favorable survival. It was primarily expressed in T cells, particularly CD8⁺ subsets, and associated with enriched immune infiltration and elevated checkpoint gene expression. IL27RA high-expression patients showed lower TIDE scores, better outcomes in ICI-treated cohorts, and higher sensitivity to multiple chemotherapeutic agents. IL27RA is a potential immune biomarker that reflects an inflamed tumor microenvironment and predicts benefit from immunotherapy and chemotherapy in breast cancer. These findings provide novel insights into immune-based stratification using single-cell transcriptomic data. Show less
Magnetic resonance imaging and circulating molecular testing are potential methods for diagnosing and treating Parkinson's disease (PD). However, their relationships remain insufficiently studied. Usi Show more
Magnetic resonance imaging and circulating molecular testing are potential methods for diagnosing and treating Parkinson's disease (PD). However, their relationships remain insufficiently studied. Using genome-wide association summary statistics, we found in the general population a genetic negative correlation between white matter tract mean diffusivity and PD (-0.17 < Rg < -0.11, p < 0.05), and a positive correlation with intracellular volume fraction (0.12 < Rg < 0.2, p < 0.05). Additionally, 1345 circulating genes causally linked with white matter tract diffusivity were enriched for muscle physiological abnormalities (padj < 0.05). Notable genes, including LRRC37A4P (effect size = 15.7, p = 1.23E-55) and KANSL1-AS1 (effect size = -15.3, p = 1.13E-52), were directly associated with PD. Moreover, 23 genes were found linked with genetically correlated PD-IDP pairs (PPH4 > 0.8), including SH2B1 and TRIM10. Our study bridges the gap between molecular genetics, neuroimaging, and PD pathology, and suggests novel targets for diagnosis and treatment. Show less
Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore t Show more
Obesity-induced metabolic inflammation is a key driver of chronic kidney disease (CKD), with immune dysregulation, particularly among lymphocytes, contributing to early disease pathology. To explore the role of apolipoprotein A4 (Apoa4) in regulating immune cell metabolism and function, we establish high-fat diet-induced obese (DIO) models using wild-type and Show less
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to Show more
The existing evidence regarding the impact of tamoxifen on lipoprotein(a) and apolipoproteins remains inconsistent. Therefore, this updated meta-analysis of randomized controlled trials (RCTs) aims to enhance the quality of evidence concerning the effects of tamoxifen on these lipid parameters. Eligible RCTs published up to October 2024 were meticulously selected through a comprehensive search. A meta-analysis was then performed using a random-effects model, and results were presented as the weighted mean difference (WMD) with a 95% confidence interval (CI). Findings from the random-effects model revealed an increase in ApoA-I (WMD: 15.22 mg/dL, 95% CI: 6.43-24.01, P = 0.001), alongside decreases in ApoB (WMD: -9.33 mg/dL, 95% CI: -15.46 to -3.19, P = 0.003) and lipoprotein(a) (WMD: -3.35 mg/dL, 95% CI: -5.78 to -0.91, P = 0.007) levels following tamoxifen treatment in women. Subgroup analyses indicated a more significant reduction in lipoprotein(a) levels in RCTs with a duration of ≤24 weeks (WMD: -3.65 mg/dL) and in studies using tamoxifen doses of ≥20 mg/day (WMD: -4.53 mg/dL). This meta-analysis provides evidence that tamoxifen leads to a decrease in lipoprotein(a) levels, along with reductions in ApoB and increases in ApoA-I among women. Show less
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles Show more
The deer antler is a fully regenerable and the fastest-growing osseous organ. Circular RNA (circRNA), a novel member of the non-coding RNA family, has significant research potential and crucial roles in biological processes. This study aims to explore the impact and mechanisms of circRNA505 on antler chondrocytes. Functional experiments demonstrated that m5C-modified circRNA505 inhibits antler chondrocyte proliferation, enhances osteogenic differentiation, and facilitates cellular glycolysis. Mechanistically, dual luciferase and AGO2-RIP assays revealed a direct binding relationship between circRNA505, miR-127, and p53. Rescue assays further showed that circRNA505 affects cell proliferation and differentiation through the miR-127/p53 axis. Meanwhile, RNA Antisense Purification (RAP) screening and analysis of related proteins binding to circRNA505 demonstrated that circRNA505 binds to LDHA and increases the level of LDHA phosphorylation through FGFR1 to promote cellular glycolysis by FISH-IF, RIP, and Western blot experiments. Additionally, Me-RIP assays confirmed the m5C methylation modification of circRNA505. NSUN2 mediates the m5C modification of circRNA505, affecting its stability, while the m5C reader ALYREF promotes the nuclear export of circRNA505 in an ALYREF-dependent manner. This study provides new insights into the regulatory mechanisms underlying rapid antler development. Show less
Panax notoginseng saponin (PNS) has a variety of biological activities, such as improvement of myocardial ischemia, improvement of learning and memory, hypolipidemia, and immunomodulation. However, it Show more
Panax notoginseng saponin (PNS) has a variety of biological activities, such as improvement of myocardial ischemia, improvement of learning and memory, hypolipidemia, and immunomodulation. However, its protective mechanism on the central nervous system (CNS) is not clear. The present study initially evaluated the possible mechanism of PNS to improve cognitive dysfunction due to chronic sleep deprivation (CSD). In the present study, we used a modified multi-platform aquatic environment sleep deprivation method to induce a cognitively impaired rat model, and explored the mechanism of action of PNS by integrating serum metabolomics and network pharmacology, which was further verified by molecular docking and experiments. The results showed that PNS significantly shortened the escape latency, increased the target quadrant time and the number of traversing platforms, and attenuated the inflammatory damage in the hippocampal Cornu Ammonis 1 (CA1) region in CSD rats. The non-targeted metabolomics results indicated that 35 biomarkers significantly altered following PNS therapy intervention, with metabolic pathways enriched for the effects of One carbon pool by folate, Riboflavin metabolism, Glycerophospholipid metabolism, Sphingolipid metabolism, Glycerolipid metabolism, Arachidonic acid metabolism, and Tryptophan metabolism. In addition, network pharmacology identified 234 potential targets for PNS intervention in CSD with cognitive impairment. Metabolite-response-enzyme-gene network was constructed by MetaScape and matched with the network pharmacology results to identify a total of five shared targets (LPL, GPAM, HSD11B1, HSD11B2, and SULT2A1) and two metabolic pathways (Sphingolipid metabolism and Steroid hormone biosynthesis). The results of molecular docking revealed that the five active ingredients had good binding ability with the five core targets. qPCR analysis confirmed the ability of PNS to modulate the above five targets. The combination of metabolomics and network analysis provides a scientific basis for promoting the clinical application of PNS in cognitive impairment. Show less
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusi Show more
Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusion partner distribution, and unique kinase domain distribution. We conducted a multicenter study to comprehensively profile FGFR fusions in the largest Chinese pan-cancer cohort to date, comprising 118 FGFR fusions from 114 individuals. Both DNA- and RNA-based sequencing approaches were utilized to reveal novel and fundamental features of FGFR fusion. Our research reveals an incidence rate of 0.96% for FGFR rearrangements within this Chinese cohort, including a high incidence rate of FGFR fusions (40%) in parotid gland carcinoma. However, this is based on a small sample size of 5 tumors and should be interpreted cautiously pending validation in larger cohorts. We also uncovered distinct breakpoint distribution patterns across various FGFR rearrangements. For example, a primary breakpoint in intron17 of FGFR2 was predominant (21/22), while FGFR1/3 breakpoints displayed substantial diversity. For the first time, we identified "hot" breakpoints in FGFR1 intron17, exon18, and FGFR3's 3' untranslated region. These findings underline the importance of incorporating these regions in targeted sequencing to ensure comprehensive detection of FGFR1/3 fusions. Notably, we observed a predilection for intrachromosomal distribution in common FGFR1/2/3 fusions. In contrast, most novel fusions (12/15) exhibited an interchromosomal distribution pattern, indicating variations in the fusion formation mechanism. Importantly, our study demonstrates the substantial incremental value of RNA-NGS or other orthogonal methods in confirming the functionality of FGFR rearrangements initially identified by DNA sequencing. In our cohort, 46% (6/13) of rare FGFR1/2/3 fusions lacked detectable RNA transcripts; however, this does not definitively indicate non-functionality as factors such as low RNA quality, expression below detection limits, or nonsense-mediated decay may contribute. Therefore, RNA-based validation is critical for accurately identifying potentially targetable FGFR fusions and guiding therapy. Our findings offer critical novel insights into functional FGFR fusions and bear considerable clinical implications for identifying individuals whose tumors are most likely to respond favorably to FGFR-targeted therapies. Show less
Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report Show more
Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of mitochondrial morphology and function, and BACE1 mRNA decay relative to amyloid deposition. We then identify a small molecule CN-0928 that inhibits the condensates by reducing PCBP2 protein level and mitigates AD pathology and cognitive decline, in which CN-0928 binding to a target protein integrator complex subunit 1 (INTS1) allows to regulate PCBP2 expression. Our findings place PCBP2 condensates as a key player that cooperates the seemingly disparate but important pathways, and show pharmacological modulation of PCBP2 as an effective approach for treating AD. Show less
Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. H Show more
Dual-specificity protein phosphatase 6 (DUSP6), also known as mitogenactivated protein kinase phosphatase 3 (MKP-3), was considered as a functional candidate gene for white fat accumulation in mice. However, the physiological function of the DUSP6 gene on white adipocyte adipogenesis in farm animals remains unknown. In this study, we aimed to clarify the effect of DUSP6 on porcine subcutaneous preadipocyte proliferation and differentiation. We first make clear that the patterns of DUSP6 expression is associated with fat contents in porcine fat deposition related tissues. Porcine subcutaneous preadipocytes were isolated and induced to differentiation. Small interfering RNAs were applied to deplete DUSP6. MTT assay, CCK-8 analysis, Oil Red O staining, triglyceride determination and reverse transcription quantitative polymerase chain reaction were applied to study the regulatory role of DUSP6 during adipocyte adipogenesis in pigs. We found that the expression levels of DUSP6 were significantly higher in backfat and longissimus dorsi tissues from fat-type pigs than in those from lean-type pigs. Consistently, the significantly induced expression of DUSP6 was also observed in differentiated adipocytes. In addition, knockdown of DUSP6 greatly inhibited preadipocytes proliferation, through the decreased cell viability and downregulated mRNA expressions of cell proliferation-associated genes, including PCNA, CDK1, CDK2. Furthermore, knockdown of DUSP6 significantly inhibited preadipocytes differentiation, as evidenced by markedly reduced lipid droplet formation, attenuated triglyceride accumulation and downregulated expression levels of adipogenic transcription masters (PPARγ, C/EBPβ, FASN and FABP4) in DUSP6 knockdown cells. Our results demonstrate that DUSP6 is required for white adipocyte adipogenesis in pigs. Show less
DHAV-3 is one of the main causative agents of duck viral hepatitis (DVH), an acute and highly lethal infectious disease in duck industry. However, the understanding of the pathogenesis of this virus i Show more
DHAV-3 is one of the main causative agents of duck viral hepatitis (DVH), an acute and highly lethal infectious disease in duck industry. However, the understanding of the pathogenesis of this virus in ducklings is limited. To dissect the molecular characteristics associated with pathobiology of ducklings to DHAV-3, we applied single-cell RNA-sequencing approach to profile the transcriptome of 1.4 million cells from 14 livers of DHAV-3 susceptible (S) and resistant (R) ducklings during viral infection and 4 uninfected healthy controls. We found that infected S ducks exhibited the activation of type I and II interferon pathways with elevated expression of interferon-stimulated genes (ISGs) compared to infected R ducks and healthy controls. DHAV-3 promoted proinflammatory phenotype and inhibited the cell apoptosis pathway of Kupffer cells of S ducks. Furthermore, we observed the elevated expression of host factor PLAC8 in S ducks and validated its ability to facilitate the infection of DHAV-3. We identified significant dysregulation of various genes in complement and coagulation cascades in hepatocytes2 exclusive to S ducks, together with over-secretion of ANGPTL4 from endothelial cells in S ducks which is confirmed to promote cellular migration, suggesting etiology of coagulopathic complications in ducks with severe DVH. Collectively, this study provides a rich resource for understanding the inflammatory immune signatures and cell communications underlying the pathogenesis of DHAV-3 infection, which may accelerate the development of better diagnostic methods and strategies for controlling this disease. Show less
Sow colostrum is rich in lactoferrin (LF), which can be orally administered to protect piglets from porcine epidemic diarrhea virus (PEDV) infection, thereby reducing piglet mortality. Previous study Show more
Sow colostrum is rich in lactoferrin (LF), which can be orally administered to protect piglets from porcine epidemic diarrhea virus (PEDV) infection, thereby reducing piglet mortality. Previous study has shown that sows fed with recombinant B. subtilis expressing 4,4-diaponeurosporene (B.S-Dia) have significantly higher LF levels in their colostrum compared to sows fed with B. subtilis. This suggests that 4,4-diaponeurosporene (DNP) produced by B.S-Dia may influence LF content in sow colostrum. In this study, we first extracted DNP expressed by the recombinant probiotic using acetone-hexane extraction. Flow cytometry, RT-qPCR, and ELISA analyses demonstrated that DNP promoted dendritic cell (DCs) maturation and increased the expression of IL-1β and IL-27. We then established a method for isolating neutrophils from sow colostrum and set up a co-culture system of neutrophils and DCs to investigate factors regulating LF secretion. The results indicated that DCs secretions enhanced LF expression in neutrophils. Finally, the application of IL-27 inhibitors confirmed that IL-27 produced by DCs upregulates LF secretion in neutrophils. These findings elucidate the mechanism by which DNP promotes LF production in colostrum and provide a theoretical foundation for using B.S-Dia to prevent and control PEDV infection in piglets. Show less
Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performe Show more
Altered levels of human plasma metabolites have been implicated in the etiology of bipolar disorder (BD). However, the causality between metabolites and the disease was not well described. We performed a bidirectional metabolome-wide Mendelian randomization (MR) analysis to evaluate the potential causal relationships between 871 plasma metabolites and BD. We used DrugBank and ChEMBL to evaluate whether related metabolites are potential therapeutic targets. Finally, Bayesian colocalization analysis was performed to identify shared genomic loci BD and identified metabolites. Our MR results showed that six metabolites were significantly associated with a reduced risk of BD, including arachidonate (20:4n6) (OR: 0.90, 95% CI: 0.84-0.95) and sphingomyelin (d18:2/24:1, d18:1/24:2) (OR: 0.92, 95% CI: 0.87-0.96), while five metabolites were significantly associated with an increased risk of BD, including 1-palmitoyl-2-linoleoyl-GPE (16:0/18:2) (OR: 1.09, 95% CI: 1.05-1.13). However, our reverse MR analysis showed that BD was not associated with the levels of any metabolite. Additionally, the leave-one-out analysis revealed SNPs within chromosome 11 loci harboring MYRF, FADS1, and FADS2 as ones with the potential to influence partial causal effects. Druggability evaluation showed that 10 of the BD-related metabolites, such as sphingomyelin and cytidine, have been targeted by pharmacologic intervention. Colocalization analysis highlighted one colocalized region (chromosome 11q12) shared by 11 metabolites and BD and pointed to some genes as possible players, including FADS1, FADS2, FADS3, and SYT7. Our study supported a causal role of plasma metabolites in the susceptibility to BD, and the identified metabolites may provide a new avenue for the prevention and treatment of BD. Show less
To clarify the possible mechanism of leptin and α-MSH on the onset of puberty in female offspring rats after prenatal androgen exposure. Sixteen 8-week-old specific pathogen free (SPF) healthy Sprague Show more
To clarify the possible mechanism of leptin and α-MSH on the onset of puberty in female offspring rats after prenatal androgen exposure. Sixteen 8-week-old specific pathogen free (SPF) healthy Sprague Dawley (SD) pregnant rats were randomly divided into the testosterone-treated group (TG, female offspring termed PNA group) or the olive oil control group (OOG, female offspring termed VEH group). The female offspring rats of two groups were raised to 21 days (PND21) and weaned. Six female offspring rats at PND21 (VEH:PNA = 3:3) were randomly selected for transcriptome sequencing. Twenty-seven offspring female rats were randomly divided into three groups (VEHI:VEHII:PNA = 9:9:9). VEHI group was observed until the onset of puberty, VEHII and PNA groups were observed until the 8th week. Compared with VEH group, onset of puberty was not observed in PNA group, and hypothalamic Pomc gene expression at PND21 was lower. Compared with the VEHI group, the body weight, abdominal fat, serum testosterone (T), dehydroepiandrosterone (DHEA) and leptin (LEP) levels were upregulated in the PNA group, while serum gonadotropin-releasing hormone (GnRH), mRNA of hypothalamic estrogen receptor α (ERα), α-melanocyte stimulating hormone (α-MSH), melanocortin receptor-4 (MC4R), GnRH and adipose AR, and the protein of androgen receptor (AR) and leptin receptor (LEPR) in the hypothalamic arcuate nucleus (ARC) were decreased. In the PNA group, there were positive correlations between serum DHEA and mRNA of hypothalamic ERα, MC4R and AR, negative correlations between mRNA of adipose AR and serum T and free testosterone (FT). Prenatal androgen exposure delayed the onset of puberty in female offspring, the possible mechanism of which is that prenatal androgen exposure may increase the levels of androgen and LEP, decreases their sensitivity and the expression of AR, LEPR, and MC4R, reducing GnRH secretion. Show less
Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, o Show more
Diabetic cardiomyopathy (DCM) in type 2 diabetes (T2D) may lead to heart failure and patient death. Fibroblast growth factor 21 (FGF21) is a therapeutic candidate for treating this disease. However, one impediment to its clinical use is its weak ability to activate downstream signaling pathways. In this study, based on our in-depth understanding of the binding properties of fibroblast growth factor receptor 1c (FGFR1c) with paracrine FGF1 and endocrine FGF21, we engineered a novel FGF21 analog named FGF21 Show less
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progress Show more
Vaccinia-related kinase 1 (VRK1) is involved in numerous cellular processes, including DNA repair, cell cycle and cell proliferation. However, its roles and molecular mechanism underlying the progression of hepatocellular carcinoma (HCC) are yet largely unexplored. Here, we demonstrated that VRK1 expression is elevated in HCC tumor tissues, which is associated with high tumor stage and poor prognosis in HCC patients. In vitro and in vivo experiments manifested that VRK1 overexpression significantly promotes cell proliferation, colony formation, migration and tumor growth of HCC by inducing epithelial-mesenchymal transition (EMT) program. Mechanistically, immunoprecipitation combined with mass spectrometry analysis determined that VRK1 interacts with CHD1L, which mediates the phosphorylation of CHD1L at serine 122 site. RNA-seq revealed that one of the key downstream target genes of VRK1 is SNAI1, by which VRK1 promotes EMT process and HCC progression. Furthermore, VRK1 upregulates SNAI1 expression through phosphorylating CHD1L. In conclusion, these findings suggested that VRK1/CHD1L/SNAI1 axis acts as a cancer-driving pathway to promote the proliferation and EMT of HCC, indicating that targeting VRK1 may be an attractive therapeutic strategy of HCC. Show less